2. Academic Validation
  3. N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia

N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia

  • J Med Chem. 2022 Aug 25;65(16):11241-11256. doi: 10.1021/acs.jmedchem.2c00788.
Justin S Cisar 1,  Christine Pietsch 1,  Lindsey G DeRatt 1,  Edgar Jacoby 2,  Faraz Kazmi 1,  Colleen Keohane 1,  Katie Legenski 1,  Rosalie Matico 1,  Paul Shaffer 1,  Yvan Simonnet 1,  Alexandra Tanner 1,  Chao-Yuan Wang 1,  Weixue Wang 1,  Ricardo Attar 1,  James P Edwards 3,  Scott D Kuduk 1
Affiliations

Affiliations

  • 1 Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States.
  • 2 Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 3 Janssen Research and Development, San Diego, California 92121, United States.
PMID: 35925768 DOI: 10.1021/acs.jmedchem.2c00788
Abstract

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate Dehydrogenase (DHODH) is an Enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

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